DISCUSSION
In this study we analyzed the diagnostic and management patterns of
children with AIFR over the past 15 years and their implications on
outcomes. While still considered an extremely aggressive disease with
dismal prognosis, the results of this study showed a significant
increase in patients’ survival in the past decade compared to earlier
years. AIFR had historically been associated with high mortality rates
of 50%–90%16. Recently published data indicated
better prognosis with mortality rates of 30-50% which was attributed
mainly to early detection of AIFR17 and aggressive
surgical management18. In the present study, the
overall mortality rate was 38%, and the disease-specific mortality rate
was 26%. Nonetheless, no patient has died of AIFR since 2012.
The status of the underlying disease was previously shown to be among
the leading prognostic factors4,19. Hematologic
malignancies, most notably ALL and AML, were reported to be the leading
causes of immunosuppression3,4. The decrease in
overall mortality rate in our study may reflect better control of the
underlying disease, which may have contributed to the change in
AIFR-specific survival. The majority of patients (68%) developed AIFR
during disease remission, and as expected, had better overall survival
outcomes compared to patients with non-complete remission. These data
highlight the importance of better control of the immunosuppressive
state to improve the prognosis of patients with AIFR.
Early diagnosis and aggressive surgical treatment of AIFR have been
proven to be critical in improving patients’
outcomes20. In the present study a low threshold for
diagnosis led to early investigation and surgical intervention within a
median of 4 days from the onset of fever. In 71% of our patients,
multiple surgical procedures were performed, and debridement was
repeated until no further disease progression was observed. Moreover,
along with the improvement in technology and experience, a more
aggressive surgical approach was adopted in our institution in the
latter years of the study including pterygopalatine fossa, infratemporal
fossa and skull base debridement as needed, which may have been
associated with the improved survival, observed in recent years.
Novel detection methods and newer systemic antifungal therapies may also
have contributed to improved patient survival. Culture studies had long
been considered the gold standard for identification of the culprit
subspecies in AIFR, but their reported sensitivity was low (30-54%),
and their diagnostic value was further limited by the slow growth rate
of fungal pathogens, leading to delays in appropriate antifungal
therapy20,21. Since PCR first came into use in our
practice in 2011, it has become a leading detection method, and was used
in >90% of cases. Although recognized as an augmenting
tool to improve diagnosis of AIFR, PCR was not included in the revised
definitions of invasive fungal disease published in 2008, because the
technique had not yet been clinically validated22.
More recent data, however, have shown that with the advantage of rapid
detection of mixed infection in a single specimen, panfungal PCR is more
sensitive and specific than cultures and direct sequencing in patients
with fungal rhinosinusitis8. In our practice, we found
panfungal PCR to be superior to fungal cultures in the detection of
pathogens and to be associated with a change of treatment in nearly
one-fifth of cases.
Historically, AmB has been considered the drug of choice for treatment
of invasive fungal infections, and it remains the agent with the
broadest antifungal spectrum23. However, its use has
become limited due to high incidence of adverse effects and substantial
risk of nephrotoxicity which led to adaptations of
therapy23,24. With improved safety profile and greater
efficacy, novel agents such as liposomal AmB, triazoles and
echinocandins have gradually become the drugs of choice for invasive
fungal infections10,22,24,25. In the current study,
since 2011 AmB, which was associated with decreased survival, has been
replaced as the treatment of choice by liposomal AmB, and novel
triazoles and echinocandins. We believe that this may have contributed
to the improved survival in recent years.
The main limitations of this study include its retrospective design and
small cohort size. Nonetheless, the study’s duration period enabled us
to view with perspective the trends in management and survival of
children with AIFR.